Role of angiotensinogen in blood pressure homeostasis.

Gardes, J.; Bouhnik, J; Clauser, Éric; Corvol, Pierre; Ménard, Joël

doi:10.1161/01.hyp.4.2.185

Cited by 78 publications

(40 citation statements)

References 20 publications

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“…Several early studies showing a positive correlation of plasma AGT levels with blood pressure, 44 decreased blood pressure with administration of anti-AGT antibodies, 45 increased blood pressure with injection of AGT, 46 and elevated blood pressure in animals with AGT transgenes 47 offered compelling evidence linking AGT to hypertension. However, the most compelling early genetic evidence implicating this gene in essential hypertension in humans came from the study of Jeunemaitre et al 5 showing linkage between a marker downstream of the AGT gene and hypertension in affected sibships of Northern and Western European descent.…”

Section: A Genetic Link Between Hypertension and Agt?mentioning

confidence: 99%

Genetic Basis of Hypertension

2006

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H ypertension is a common and complex human disease that causes significant morbidity and mortality worldwide. Unfortunately, despite recent advances in understanding and treating hypertension, its prevalence continues to rise. Across the globe, Ϸ26% of the adult population experiences hypertension, and Kearney et al 1 estimate that this could rise to Ϸ29% by the year 2025. According to the American Heart Association, one third of the United States adult population is hypertensive, and one third of these remain undiagnosed. Hypertension is the most common risk factor for stroke and myocardial infarction and predisposes affected individuals to heart failure, ventricular arrhythmias, renal failure, blindness, and other serious medical problems, resulting in Ϸ22 000 deaths each year in the United States.Essential hypertension accounts for Ϸ90% of hypertensive cases and is the 13th leading cause of death in the United States. Factors that may predispose a person to essential hypertension include weight, age, sex, ethnicity, physical activity, diet, cigarette smoke, stress, hormones, other medical conditions (eg, diabetes), and, of course, genetics. Indeed, studies of ambulatory blood pressure measurements in twins suggest that essential hypertension has a strong genetic component. 2 However, the fact that patients often differentially respond to diverse classes of antihypertensive medications indicates that the etiology of hypertension likely varies considerably among patients, especially when large populations are considered. 3 Consequently, researchers must attempt to tease out what must be a dynamic interplay among heterogeneous genetic backgrounds, diverse environmental factors, and differential etiologies in the pathogenesis of this disorder, all of which make attempts to understand the genetic basis of hypertension a challenge.In this review, we will revisit the evidence supporting or refuting an association of the angiotensinogen (AGT) gene with hypertension. We will begin by describing the basics of the AGT gene and protein, followed by some of the known physiological roles of the classical and tissue renin-angiotensin system (RAS) in blood pressure regulation. A rationale for the implication of AGT in essential hypertension will be subsequently presented, emphasizing the role of linkage analyses and association studies. Particular attention will be given to the role of AGT gene polymorphisms in the etiology of essential hypertension. The reader is forewarned, however, that interpretation of the hypertension genetics literature is complicated, because it is replete with apparently conflicting results obtained largely from association studies using the case-control design. Whereas some of the disagreement among reports must arise from the factors discussed above (ie, genetic, etiologic, and environmental heterogeneity), a substantial proportion may be because of poorly defined inclusion criteria or inadequate appreciation of the importance of statistical power and replication. A critical review of the topic s...

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Section: A Genetic Link Between Hypertension and Agt?mentioning

confidence: 99%

Genetic Basis of Hypertension

2006

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“…10,11 Injection of angiotensinogen increases blood pressure, 12 whereas antibodies against angiotensinogen decrease blood pressure. 13 Hypertensive persons with the TT genotype compared with the MM genotype at M235T had higher systolic and diastolic blood pressure and plasma angiotensinogen levels, and they were 1.6 times more likely to use an antihypertensive medication and 2.1 times more likely to use 2 antihypertensive medications. 14 In addition to the genetic evidence from the above studies, it has been suggested that the angiotensinogen gene influences the salt sensitivity of blood pressure.…”

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Angiotensinogen Genotype, Sodium Reduction, Weight Loss, and Prevention of Hypertension

et al. 1998

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Abstract-The angiotensinogen gene has been linked to essential hypertension and increased blood pressure. A functional variant believed to be responsible for hypertension susceptibility occurs at position Ϫ6 in the promoter region of the gene in which an A for G base pair substitution is associated with higher angiotensinogen levels. To test whether an allele within the angiotensinogen gene is related to subsequent incidence of hypertension and blood pressure response to sustained sodium reduction, 1509 white male and female subjects participating in phase II of the Trials of Hypertension Prevention were genotyped at the angiotensinogen locus. Participants had diastolic blood pressures between 83 and 89 mm Hg and were randomized in a 2ϫ2 factorial design to sodium reduction, weight loss, combined intervention, or usual care groups. Persons in the usual care group with the AA genotype at nucleotide position Ϫ6 had a higher 3-year incidence rate of hypertension (44.6%) compared with those with the GG genotype (31.5%), with a relative risk of 1. 1,2 Multiple polymorphisms were examined for association with hypertension in an attempt to identify a specific mutation that could cause increased expression of angiotensinogen levels leading to increased blood pressure. The two polymorphisms receiving the most attention were a methionine-to-threonine amino acid substitution at amino acid 235 (M235T) in the mature angiotensinogen protein and a threonine-to-methionine substitution at amino acid 174 (T174 M).1,3 These amino acid substitutions arise from nucleotide substitutions at positions ϩ704 and ϩ521, respectively, from the transcription start site. The strongest evidence for association has been with the M235T polymorphism. However, this polymorphism is not near the cleavage site where renin acts on angiotensinogen to form angiotensinogen I, nor is it thought that this amino acid substitution plays a functional role. Because of this and the lack of consistency in association studies of M235T with hypertension, 2,4-6 it was suspected that there may be another site in linkage disequilibrium with M235T that is a causal mutation. Recently, evidence was published that an A for G nucleotide substitution in the promoter region of the angioten-

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“…Thus, this revised concept predicts that plasma levels of angiotensin largely represent a spillover from the tissue sites of production (15). That plasma angiotensins predominantly result from the action of kidney-derived renin on plasma (liver-derived) angiotensinogen is shown by the fall in plasma angiotensin levels that follows nephrectomy (16)(17)(18)(19), and by the hypotensive effect of anti-angiotensinogen antibodies when injected into either sodium-replete or sodium-deplete rats (20). Given this local production ofAl and All by the circulating RAS, it is apparent that such local production may be subject to tissue-specific mechanisms of regulation, which cause changes in local All concentration that are not reflected in the plasma concentrations of renin or All.…”

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Circulating and tissue angiotensin systems.

Campbell¹

1987

J. Clin. Invest.

565

167

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Angiotensin has many different actions, most of which relate, either directly or indirectly, to the regulation of blood pressure, fluid, and electrolyte homeostasis (1, 2). In addition to potent vasoconstrictor effects, actions ofangiotensin on vasculature include the stimulation ofprostaglandin release (3), the modulation of angiotensin receptor number (4), and the stimulation of angiogenesis (5). Angiotensin also has important actions on the central and peripheral nervous systems, the adrenal, kidney, intestine, and heart (6-1 1). Given these multiple diverse actions of angiotensin, two important questions are (a) which of these actions represent normal physiological events, and (b) whether such actions may assume a pathogenic role. These questions have recently been placed in sharper focus by the clinical application of inhibitors of the renin-angiotensin system (RAS),' and in particular, the use of converting enzyme inhibitors (CEIs) for the treatment of hypertension. Any attempt to answer these questions requires an accurate concept ofthe RAS. The purpose ofthis review is to discuss new concepts concerning angiotensin production by the circulating RAS, how these relate to angiotensin production within tissues, and the possible mechanisms by which CEIs lower blood pressure. The study of tissue angiotensin systems is still at an early stage. In this review I have attempted to synthesize a coherent model of the interaction between the circulating and tissue angiotensin systems, which might assist in the interpretation of new developments in this area. Circulating RASAt the present time, the prevailing view holds that the circulating RAS is primarily an endocrine system designed for the general mediation, through the systemic circulation, of the effects of renin on angiotensin production in plasma (12,13). This concept can be summarized as follows: renin released by the kidney circulates in plasma, where it cleaves angiotensinogen to generate angiotensin I (Al).

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Role of angiotensinogen in blood pressure homeostasis.

Cited by 78 publications

References 20 publications

Genetic Basis of Hypertension

Genetic Basis of Hypertension

Angiotensinogen Genotype, Sodium Reduction, Weight Loss, and Prevention of Hypertension

Circulating and tissue angiotensin systems.

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